Abstract
The microtubule-stabilizing drug epothilone B (epoB) has shown potential value in the treatment of spinal cord injury (SCI) through diverse mechanisms. However, it remains elusive why a limited overall effect was observed. We aim to investigate the limiting factors underlying functional recovery promoted by epoB. The same SCI model treated by epoB was established as discussed previously. We used a cerebrospinal fluid (CSF) sample to assess the changes in cytokines in milieu of the SCI lesion site after epoB treatment. We then analyzed the source of cytokines, the state of microglia/macrophages/monocytes (M/Ms), and the recruitment of neutrophil in the lesion site by using the results of antibody array. Following these findings, we further evaluated the motor functional recovery caused by the reshaped microenvironment. Systemic administration of epoB significantly increased levels of several cytokines in the CSF of the rat SCI model; macrophage colony-stimulating factor (M-CSF) secreted by intact central nervous system (CNS) cells was one of the cytokines with increased levels. Along with epoB and other cytokines, M-CSF reshapes the SCI milieu by activating the microglias, killing bone marrow-derived macrophages, polarizing the M/M to M1 phenotype, and activating downstream cytokines to exacerbate the SCI injury, but it also increases the expression of neurotrophic factors. Anti-inflammatory therapy using a neutralizing antibody mix shows encouraging results. Using in vivo experiments, our findings indicate that epoB inhibits the SCI functional recovery in many ways by reshaping the milieu, which counteracts the therapeutic efficacy that led to the limited overall effectiveness.
Highlights
Epothilone B is an ideal drug for the treatment of spinal cord injury (SCI), which can reduce scar formation in the lesion site, reactivate the axons’ regeneration potential, and is convenient for operation.[1]
Because biologically active cytokines of SCI milieu exist in the SCI lesion mainly, and the cytokines of SCI lesion differ very little with cerebrospinal fluid (CSF), we assessed the profiles of expression of cytokines by cytokine protein array with CSF from the SCI model treated with Epothilone B (epoB) (n = 3) or solvent control (n = 3)
EpoB-treated SCI rats were only macrophage colony-stimulating factor (M-CSF) elevated compared with the control at 1 day post epoB treatment (DPE) (Figures 1a and e); both anti- and proinflammatory molecules including interleukin-1α (IL-1α), IL-4, M-CSF, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β) were elevated in the CSF of epoB-treated SCI models at 3 DPE (Figures 1b and f)
Summary
Epothilone B (epoB) is an ideal drug for the treatment of spinal cord injury (SCI), which can reduce scar formation in the lesion site, reactivate the axons’ regeneration potential, and is convenient for operation.[1]. Received 07.5.17; revised 30.8.17; accepted 12.9.17; Edited by A Verkhratsky epoB suppresses SCI functional recovery by killing bone marrow-derived macrophages (BMDMs), activating microglia, polarizing M/M to M1 phenotype, and recruiting neutrophils to increased lesion inflammation burden. Unlike previous reports, these effects retarded the functional recovery after SCI. To clarify the biological effects of elevated M-CSF in milieu, we need to identify the value, duration, and cell origin of elevated M-CSF at first
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